Alzheimer's disease - the most common age-related neurodegenerative disorder - is a personal and societal tragedy of immense and growing proportions. Over 5 million Americans currently suffer from Alzheimer's disease (AD), and the number is expected to triple by 2050. Despite recent progress in characterizing AD, therapeutic interventions have been disappointing in large part because we lack a complete understanding of the mechanisms that contribute to this disease. Research suggests that peripheral inflammation is an important and modifiable risk factor for AD, and epidemiologic studies suggest that mid-life metabolic syndrome, obesity, and hypertension are inter-related health care conditions that increase the risk of age-related neurodegenerative disorders, particularly AD. The mechanistic links between these systemic disorders and neurodegeneration are poorly understood, but may be the key to developing effective anti-AD therapeutics. These risk factors are particularly prevalent in African Americans, who are also at increased risk for AD. The novel overarching hypothesis of this proposal is that chronic systemic disorders (i.e. metabolic syndrome and hypertension) are mechanistically linked to AD through a multistage process that involves dysregulation of the renin angiotensin system (RAS), systemic inflammation and a heightened peripheral immune response, followed by increased immune cell trafficking across the blood brain barrier (BBB) and leading to chronic neuroinflammation, CNS dysfunction, and cognitive decline. To test this hypothesis, we have assembled an interdisciplinary team of experts in inflammation, RAS dysfunction and neurodegeneration to address the following questions: 1) What is the relationship between chronic peripheral inflammation and Alzheimer-like pathology in a transgenic mouse model of Alzheimer-like pathology? 2) How is overactivation of the renin-angiotensin system related to brain inflammation, immune function and AD-like pathogenesis in this model? and 3) How is RAS dysfunction related to central inflammation and immune function in humans at risk for AD? In addressing the third question we will focus on African Americans, who are particularly vulnerable to metabolic syndrome and AD yet have received little attention in systematic investigations. Successful completion of the proposed studies will provide new and potentially paradigm- shifting mechanistic information on how diet- and hypertension-induced chronic peripheral inflammation and chronic brain inflammation contribute to the development of AD.